Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis

• DOI: 10.1371/journal.pgen.1009112
• Publication Date: 2021-04-05T17:39:11Z
• Authors: Lucilla Pizzo; Micaela Lasser; Tanzeen Yusuff; Matthew Jensen; Phoebe Ingraham; Emily Huber; Mayanglambam Dhru...; Connor Monahan; Janani Iyer; Inshya Desai; Siddharth Karthik...; Dagny J. Gould; Sneha Yennawar; Alexis T. Weiner; Vijay Kumar Pounraja; Arjun Krishnan; Melissa M. Rolls; Laura Anne Lowery; Santhosh Girirajan
• Keywords: Ubiquitin-Protein Ligases; QH426-470; 03 medical and health sciences; Genetics; Animals; Drosophila Proteins; Humans; Adaptor Proteins, Signal Transducing; 0303 health sciences; PTEN Phosphohydrolase; Brain; Gene Expression Regulation, Developmental; Nuclear Proteins; Epistasis, Genetic; Methyltransferases; DNA-Binding Proteins; Disease Models, Animal; Drosophila melanogaster; Neurodevelopmental Disorders; Calcium Channels; Chromosome Deletion; Cell Adhesion Molecules; Chromosomes, Human, Pair 16; Research Article; Transcription Factors

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly carrier parents. hypothesized the sensitizes genome for disease, while “second-hits” in genetic background modulate phenotypic trajectory. To test this model, we examined how defects conferred by knockdown individual homologs are modulated simultaneous “second-hit” genes Drosophila melanogaster Xenopus laevis . observed affect domains, leading delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite axonal morphology, cellular proliferation defects. Compared within 16p11.2 deletion, which has higher de novo occurrence, were less likely interact each other models or human brain-specific interaction network, suggesting interactions may confer impact towards phenotypes. Assessment 212 pairwise between 76 patient-specific (such as ARID1B CACNA1A ), pathways PTEN UBE3A transcriptomic targets DSCAM TRRAP ) 63% tested pairs. In 11 out 15 families, enhanced suppressed effects one many 32/96 combinations tested. fact, SETD5 synergistically interacted MOSMO both X , modified phenotypes, well axon outgrowth not either homolog. Our results suggest several sensitize defects, complex determine ultimate manifestation.